RENAL CELL CARCINOMA

Introduction
Background

Renal cell carcinoma accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. It is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy.

Increasingly, renal cell cancers are diagnosed at an earlier stage, and nephron-sparing surgery and thermal ablation are gaining acceptance as a treatment of choice for smaller tumors. Radical nephrectomy is the standard for larger and central tumors.

Recent clinical trials have established the role of targeted therapy as the first line of therapy in patients with metastatic disease. While the optimal treatment strategy continues to evolve, three agents that target angiogenesis (sunitinib, bevacizumab, and pazopanib) and an mTOR-targeted therapy (temsirolimus) have been approved as front-line agents. These have largely replaced cytokines (immunotherapy) in treatment-naive patients. Current clinical trials are testing newer agents, combinations of approved agents, and the optimal sequencing of these agents.
Pathophysiology

The tissue of origin for renal cell carcinoma is the proximal renal tubular epithelium. Renal cancer occurs in both a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET).

At least 4 hereditary syndromes associated with renal cell carcinoma are recognized: (1) von Hippel-Lindau (VHL) syndrome, (2) hereditary papillary renal carcinoma (HPRC), (3) familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS), and (4) hereditary renal carcinoma (HRC).

von Hippel-Lindau disease is an autosomal dominant syndrome that confers predisposition to a variety of neoplasms, including the following:

* Renal cell carcinoma with clear cell histologic features
* Pheochromocytoma
* Pancreatic cysts and islet cell tumors
* Retinal angiomas
* Central nervous system hemangioblastomas
* Endolymphatic sac tumors
* Epididymal cystadenomas

Renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau disease and is a major cause of death among these patients. Deletions of 3p occur commonly in renal cell carcinoma associated with VHL disease. The VHL gene is mutated in a high percentage of tumors and cell lines from patients with sporadic (nonhereditary) clear cell renal carcinoma. Several kindreds with familial clear cell carcinoma have a constitutional balanced translocation between 3p and either chromosome 6 or chromosome 8. Mutations of the VHL gene result in the accumulation of hypoxia inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor and its receptor (VEGF and VEGFR, respectively). VEGF and VEGFR are important new therapeutic targets.

Hereditary papillary renal carcinoma is an inherited disorder with an autosomal dominant inheritance pattern; affected individuals develop bilateral, multifocal papillary renal carcinoma. Germline mutations in the tyrosine kinase domain of the MET gene have been identified.

Individuals affected with familial renal oncocytoma can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. Birt-Hogg-Dube syndrome is a hereditary cutaneous syndrome. Patients with Birt-Hogg-Dube syndrome have a dominantly inherited predisposition to develop benign tumors of the hair follicle (ie, fibrofolliculomas), predominantly on the face, neck, and upper trunk, and are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.
Frequency
United States

From 1975 to 2006, the incidence of kidney cancer rose 2% annually.1 The American Cancer Society estimated that in 2009 there would be 57,760 cases (35,430 in males and 22,330 in females) of malignant tumors of the kidney diagnosed in the United States, with 12,890 deaths (8,160 in males and 4,820 in females); renal cell cancer accounted for 80% of this incidence and mortality.2

International

* Deaths worldwide from kidney cancer exceeded 100,000 in 2001.
* In most of Europe, the incidence of kidney cancer has decreased or stabilized over the past decade, perhaps in part because of reduced tobacco smoking in men. Mortality from kidney cancer has also declined in most of Europe, principally in Scandinavia and other western European countries. In men, the mortality rate per 100,000 population fell from 4.8 in 1990-1994 to 4.1 in 2000-2004; in women, the rate fell from 2.1 to 1.8.3

Mortality/Morbidity

Renal cell carcinoma is the tenth leading cause of cancer deaths in males in the United States. In men, deaths from kidney cancer decreased 3.9% between 1990 and 2005; in women, deaths decreased by 7.8% during that period. Overall, 5-year relative survival increased from 51% to 67% between 1975-1977 and 1996-2004.2 The 5-year survival rates initially reported by Robson in 1969 were 66% for stage I renal carcinoma, 64% for stage II, 42% for stage III, and only 11% for stage IV.4 Except for stage I, these survival statistics have remained essentially unchanged for several decades.
Race

Renal cell carcinoma is more common in people of Northern European ancestry (Scandinavians) and North Americans than in those of Asian or African descent. In the United States, its incidence is slightly higher among African Americans than among whites: 21.3 versus 19.2 per 100,000 population in men, and 10.3 versus 9.9 per 100,000 population in women.1
Sex

Renal cell carcinoma has a male-to-female preponderance of 1.6:1.
Age

From 2002 – 2006, the median age at diagnosis was 64 years of age1 ; however, the disease has been reported in younger people who belong to family clusters.1
Clinical
History

Renal cell carcinoma may remain clinically occult for most of its course. The classic triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease. Twenty-five to thirty percent of patients are asymptomatic, and their renal cell carcinomas are found on incidental radiologic study.

* Most common presentations
o Hematuria (40%)
o Flank pain (40%)
o Palpable mass in the flank or abdomen (25%)
* Other signs and symptoms
o Weight loss (33%)
o Fever (20%)
o Hypertension (20%)
o Hypercalcemia (5%)
o Night sweats
o Malaise
o Varicocele, usually left sided, due to obstruction of the testicular vein (2% of males)
* Renal cell carcinoma is a unique and challenging tumor because of the frequent occurrence of paraneoplastic syndromes, including hypercalcemia, erythrocytosis, and nonmetastatic hepatic dysfunction (ie, Stauffer syndrome). Polyneuromyopathy, amyloidosis, anemia, fever, cachexia, weight loss, dermatomyositis, increased erythrocyte sedimentation rate, and hypertension also are associated with renal cell carcinoma. (For more information, see Paraneoplastic Syndromes.)
o Cytokine release by tumor (eg, IL-6, erythropoietin, nitric oxide) causes these paraneoplastic conditions.
o Resolution of symptoms or biochemical abnormalities may follow successful treatment of the primary tumor or metastatic foci.

Physical

* Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
* Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass with bruit.
* Approximately 30% of patients with renal carcinoma present with metastatic disease. Physical examination should include thorough evaluation for metastatic disease. Organs involved include:
o Lung (75%)
o Soft tissues (36%)
o Bone (20%)
o Liver (18%)
o Cutaneous sites (8%)
o Central nervous system (8%)
* Varicocele and findings of paraneoplastic syndromes raise clinical suspicion for this diagnosis.

Causes
A number of environmental and genetic factors have been studied as possible causes for renal cell carcinoma.

* Cigarette smoking doubles the risk of renal cell carcinoma and contributes to as many as one third of all cases. The risk appears to increase with the amount of cigarette smoking in a dose-dependent fashion.
* Obesity is another risk factor, particularly in women; increasing body weight has a linear relationship with increasing risk.
* Hypertension may be associated with an increased incidence of renal cell carcinoma.
* Phenacetin-containing analgesia taken in large amounts may be associated with increased incidence of renal cell carcinoma.
* There is an increased incidence of acquired cystic disease of the kidney in patients undergoing long-term renal dialysis; this predisposes to renal cell cancer.
* Tuberous sclerosis
* Renal transplantation: Acquired renal cystic disease of the native kidney also predisposes to renal cell cancer in renal transplant recipients.
* VHL disease: This inherited disease is associated with renal cell carcinoma.Differential Diagnoses

Lymphoma, Non-Hodgkin
Pyelonephritis, Acute
Pyelonephritis, Chronic
Wilms Tumor
Other Problems to Be Considered

Abscess
Angiomyolipoma (benign neoplasm)
Oncocytoma (benign neoplasm)
Metastasis from distant primary
Metastatic melanoma
Renal adenoma (benign neoplasm)
Renal cyst
Renal infarct
Sarcoma
Transitional cell carcinoma of renal pelvis
Workup
Laboratory Studies

* Laboratory studies in the evaluation of renal cell carcinoma should include a workup for paraneoplastic syndromes. Initial studies are as follows:
o Urine analysis
o CBC with differential
o Electrolytes
o Renal profile
* Liver function tests (AST and ALT)
* Calcium
* Erythrocyte sedimentation rate
* Prothrombin time
* Activated partial thromboplastin time
* Other tests indicated by presenting symptoms

Imaging Studies

* A large proportion of patients diagnosed with renal cancer have small tumors discovered incidentally on imaging studies. A number of diagnostic modalities are used to evaluate and stage renal masses, including the following:
o Excretory urography
o CT scan
o Ultrasonography
o Arteriography
o Venography
o MRI
o PET
* Determining whether a space-occupying renal mass is benign or malignant can be difficult. Radiologic studies should be tailored to enable further characterization of renal masses, so that nonmalignant tumors can be differentiated from malignant ones.
* Excretory urography is not used frequently in the initial evaluation of renal masses because of its low sensitivity and specificity. A small- to medium-sized tumor may be missed by excretory urography.
* Contrast-enhanced CT scanning has become the imaging procedure of choice for diagnosis and staging of renal cell cancer and has virtually replaced excretory urography and renal ultrasound. In most cases, CT imaging can differentiate cystic masses from solid masses and supplies information about lymph node, renal vein, and inferior vena cava involvement.
* Ultrasound examination can be useful in evaluating questionable cystic renal lesions if CT imaging is inconclusive. Large papillary renal tumors are frequently undetectable by renal ultrasound.
* Renal arteriography is not used in the evaluation of a suspected renal mass as frequently now as it was in the past. When inferior vena cava involvement is suspected, either inferior venacavography or MRI angiography is used. MRI is currently the preferred imaging technique. Knowledge of inferior vena cava involvement is important in planning the vascular aspect of the operative procedure.
* A bone scan is recommended for patients with bony symptoms and an elevated alkaline phosphatase level.
* PET imaging remains controversial in kidney cancer. It has better sensitivity for detecting metastatic lesions than for determining the presence of cancer in the renal primary site.

Procedures

Percutaneous cyst puncture and fluid analysis is used in the evaluation of potentially malignant cystic renal lesions detected by ultrasonography or CT imaging.
Histologic Findings

Renal cell carcinoma has 5 histologic subtypes, as follows: clear cell (75%), chromophilic (15%), chromophobic (5%), oncocytoma (3%), and collecting duct (2%).

* Unusually clear cells with a cytoplasm rich in lipids and glycogen characterize clear cell carcinoma, which is most likely to show 3p deletion.
* Chromophilic tumors tend to be bilateral and multifocal and may have trisomy 7 and/or trisomy 17.
* Large polygonal cells with pale reticular cytoplasm characterize chromophobic carcinoma, which does not exhibit 3p deletion.
* Renal oncocytoma consists predominantly of eosinophilic cells, in a characteristic nested or organoid pattern, that rarely metastasize and do not exhibit 3p deletion or trisomy 7 or 17.
* Collecting duct carcinoma is an unusual variant characterized by a very aggressive clinical course. This tends to affect younger patients and may present as local or widespread advanced disease. These cells can have 3 different types of growth patterns, (1) acinar, (2) sarcomatoid, and (3) tubulopapillary. The sarcomatoid variant, which can occur with any histologic cell type, is associated with a significantly poorer prognosis.

Table 1. Pathologic Classification of Renal Cell Carcinoma

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Table

Cell Type


Features


Growth Pattern


Cell of Origin


Cytogenetics

Clear cell


Most common


Acinar or sarcomatoid


Proximal tubule


3p-

Chromophilic


Bilateral and multifocal


Papillary or sarcomatoid


Proximal tubule


+7, +17, -Y

Chromophobic


Indolent course


Solid, tubular, or sarcomatoid


Cortical collecting duct


Hypodiploid

Oncocytic


Rarely metastasize


Tumor nests


Cortical collecting duct


Undetermined

Collecting duct


Very aggressive


Papillary or sarcomatoid


Medullary collecting duct


Undetermined

Cell Type


Features


Growth Pattern


Cell of Origin


Cytogenetics

Clear cell


Most common


Acinar or sarcomatoid


Proximal tubule


3p-

Chromophilic


Bilateral and multifocal


Papillary or sarcomatoid


Proximal tubule


+7, +17, -Y

Chromophobic


Indolent course


Solid, tubular, or sarcomatoid


Cortical collecting duct


Hypodiploid

Oncocytic


Rarely metastasize


Tumor nests


Cortical collecting duct


Undetermined

Collecting duct


Very aggressive


Papillary or sarcomatoid


Medullary collecting duct


Undetermined
Staging

* The Robson modification of the Flocks and Kadesky system is uncomplicated and is used commonly in clinical practice. This system was designed to correlate stage at presentation with prognosis. The Robson staging system is as follows:
o Stage I - Tumor confined within capsule of kidney
o Stage II - Tumor invading perinephric fat but still contained within the Gerota fascia
o Stage III - Tumor invading the renal vein or inferior vena cava (A), or regional lymph-node involvement (B), or both (C)
o Stage IV - Tumor invading adjacent viscera (excluding ipsilateral adrenal) or distant metastases
* The tumor, nodes, and metastases (TNM) classification is endorsed by the American Joint Committee on Cancer (AJCC). The major advantage of the TNM system is that it clearly differentiates individuals with tumor thrombi from those with local nodal disease. In the Robson system, stage III disease includes both inferior vena caval involvement (stage IIIA) and local lymph node metastases (stage IIIB). Although patients with Robson stage IIIB renal carcinoma have greatly decreased survival rates, the prognosis for patients with stage Robson IIIA renal carcinoma is not markedly different from that for patients with Robson stage I or II renal carcinoma. The TNM classification system is as follows:
o Primary tumor (T)
+ TX - Primary tumor cannot be assessed
+ T0 - No evidence of primary tumor
+ T1 - Tumor 7 cm or smaller in greatest dimension, limited to the kidney
+ T2 - Tumor larger than 7 cm in greatest dimension, limited to the kidney
+ T3 - Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
+ T3a - Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
+ T3b - Tumor grossly extends into the renal vein(s) or vena cava below the diaphragm
+ T3c - Tumor grossly extends into the renal vein(s) or vena cava above the diaphragm
+ T4 - Tumor invading beyond the Gerota fascia
o Regional lymph nodes (N) - Laterality does not affect the N classification
+ NX - Regional lymph nodes cannot be assessed
+ N0 - No regional lymph node metastasis
+ N1 - Metastasis in a single regional lymph node
+ N2 - Metastasis in more than 1 regional lymph node
o Distant metastasis (M)
+ MX - Distant metastasis cannot be assessed
+ M0 - No distant metastasis
+ M1 - Distant metastasis
o AJCC stages
+ AJCC stage I - T1, N0, M0
+ AJCC stage II - T2, N0, M0
+ AJCC stage III - T1-2, N1, M0 or T3a-c, N0-1, M0
+ AJCC stage IV - T4; or any T, N2, M0; or any T, any N, M1
o The division of patients with renal cell carcinoma into low-, intermediate-, and high-risk groups with or without metastases may be useful in choosing appropriate therapy for them.Treatment
Medical Care

The therapeutic approach to renal cell carcinoma is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination. More than 50% of patients with early-stage renal cell carcinoma are cured, but the outcome for stage IV disease is poor. Thus, the approach is curative for early-stage disease. Selected patients with metastatic disease respond to immunotherapy, but many patients with advanced disease can be offered only palliative therapy.

* The treatment options for renal cell cancer are surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or combinations of these.
o Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates with chemotherapy, either single-agent or combination, are usually lower than 15%. Therefore, various biologic therapies have been evaluated.
o Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been tried, including interferon, IL-2 (aldesleukin [Proleukin]), bacillus Calmette-Guérin (BCG) vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.
* Multikinase inhibitors
o Sorafenib
+ Sorafenib (Nexavar), a small-molecule Raf kinase and vascular endothelial growth factor (VEGF) multireceptor kinase inhibitor, is approved by the U.S. Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma. This indication was based on the demonstration of improved progression-free survival in a large, multinational, randomized double-blind, placebo-controlled phase 3 study and a supportive phase 2 study.
+ The sorafenib phase 3 study was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one prior systemic treatment. Study endpoints included overall survival, progression-free survival, and response rate.
# Among 769 patients randomized, the median age was 59 years and 70% were male.
# Baseline patient and disease characteristics were well balanced. Regarding prior therapies, 93% had prior nephrectomies; 99% had received prior systemic therapies, including interleukin 2 (44%) and an interferon (68%).
# The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group (HR 0.44; 95% CI for HR: 0.35-0.55, logrank p <0.000001). Time-to-progression was similarly improved. Tumor response was determined by independent radiologic review according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Overall, of 672 patients who were able to be evaluated for response, 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partial responses.7 # Final results of this trial established the efficacy and safety of sorafenib in advanced renal cell carcinoma. Once improved progression-free survival with sorafenib had been demonstrated, patients assigned to placebo were offered sorafenib. Although an analysis that included patients who crossed over to sorafenib showed no overall survival benefit with sorafenib, a secondary analysis that did not include these patients showed significantly improved overall benefit (17.8 v 14.3 months, P = .029).8 + Sorafenib toxicities (based on an updated phase 3 study database of 902 patients) included reversible skin rashes in 40% and hand-foot skin reaction in 30%. Diarrhea was reported in 43%, treatment-emergent hypertension in 17%, and sensory neuropathic changes in 13%. Alopecia, oral mucositis, and hemorrhage also were reported more commonly on the sorafenib arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the placebo group (0.4%). + Grade 3 and 4 adverse events were unusual; only hand-foot skin reaction occurred at 5% or greater frequency in the sorafenib arm. Laboratory findings included asymptomatic hypophosphatemia in 45% versus 12% and serum lipase elevations in 41% versus 30% of sorafenib versus placebo patients, respectively. Grade 4 pancreatitis was reported in 2 sorafenib patients, although both patients subsequently resumed sorafenib, one at full dose. + Hypertension is a common side effect of sorafenib treatment, and may be high grade.9 Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib. + The recommended dose is 400 mg (two 200-mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day. + Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF; VEGFR-2,3; PDGFR-b; KIT; FLT-3; and RET. + The safety and efficacy of sorafenib were also demonstrated in a nonrandomized, open-label expanded access program in which 2,504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Patients included those with no prior therapy, nonclear cell renal cell carcinoma, brain metastases, and prior bevacizumab treatment; and elderly patients. Median overall survival was 50 weeks.10 o Sunitinib (Sutent) + Sunitinib is another multikinase inhibitor approved by the FDA for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based on the high response rate (40% partial responses) and a median time to progression of 8.7 months and an overall survival of 16.4 months. + The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR a and b. + Major toxicities (grade II or higher) include fatigue (38%), diarrhea (24%), nausea (19%), dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis occurred in 8%, and hypertension occurred in 5% of patients. + In a phase 3 study in 750 patients with previously untreated metastatic renal-cell carcinoma, PFS was longer and response rates were higher in patients who received sunitinib than in those receiving interferon alfa.11 In final survival analyses, median overall survival was greater in the sunitinib group than in the interferon-alpha group (26.4 vs. 21.8 months; P=0.051), as was the objective response rate (47% vs. 12%; P <0.001).12 + An expanded-access trial provided sunitinib on a compassionate-use basis to 4,564 trial-ineligible patients with renal cell carcinoma from countries where regulatory approval had not been granted. Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival was 18.4 months (17.4-19.2). These researchers concluded that the safety of sunitinib in these patients was manageable and its efficacy was encouraging, particularly in subgroups associated with poor prognosis (eg, those with brain metastases, low performance status, non–clear cell disease, and elderly patients).13 o Temsirolimus (Torisel) + Temsirolimus inhibits mTOR (mammalian target of rapamycin), which is a serine/threonine kinase important in the regulation of cell growth and division. Genes involved with the response to hypoxia (HIF pathway described above) are also upregulated by mTOR and are believed to be central to the pathogenesis of kidney cancers. + Temsirolimus has been tested alone and in conjunction with interferon in patients with poor prognosis advanced renal cell carcinoma. Temsirolimus monotherapy at a dose of 25 mg IV weekly resulted in longer overall and progression-free survival compared to interferon (median survival 10.9 months versus 7.3 months, P= 0.008).14 There was no significant additive effect of interferon combined with temsirolimus. A second study combining temsirolimus and interferon over a range of dose levels showed overall survival of 18.8 months and progression-free survival of 9.1 months for the combination. Partial response was observed in 8% and stable disease in 36% of patients.15 + Common toxicities of temsirolimus include asthenia, rash, anemia, hypophosphatemia, and hyperlipidemia. + Temsirolimus has FDA approval for the treatment of advanced renal cell carcinoma at a dose of 25 mg weekly IV until progression. o Everolimus (Afinitor) + Everolimus (Afinitor) is a serine-threonine kinase inhibitor of mTOR, an important regulatory protein in cell signaling. Everolimus was approved by the US Food and Drug Administration in March 2009 for advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. + In a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in patients with metastatic renal cell carcinoma that had progressed during sunitinib and/or sorafenib treatment, analysis showed significantly longer median progression-free survival with everolimus than with placebo. For everolimus, the median overall survival was 14.8 months compared with 14.4 months for placebo (hazard ratio, 0.87; P = .162); 80% of patients in the placebo arm crossed over to everolimus.16 o Other multikinase inhibitors undergoing investigation for renal cell carcinoma + Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase inhibitor that appears to have efficacy in the treatment of tumors, including renal cell carcinoma, which overexpress EGFR. A phase 3 study in patients with advanced renal cell carcinoma who had failed prior therapy found that lapatinib was well tolerated and had overall efficacy equivalent to that of hormonal therapy.17 + The novel combination of bevacizumab (a neutralizing monoclonal antibody to VEGF) and interferon has been shown to have activity against metastatic RCC.18 Completion of this phase 3 trial by Escudier et al found bevacizumab plus interferon alfa-2a effective as first-line treatment in patients with metastatic RCC.19 * Chemotherapy o A phase 2 trial of weekly intravenous gemcitabine (600 mg/m2 on days 1, 8, and 15) with continuous infusion fluorouracil (150 mg/m2/d for 21 d in 28-d cycle) in patients with metastatic renal cell cancer produced a partial response rate of 17%. No complete responses were noted. Eighty percent of patients had multiple metastases, and 83% had received previous treatment. The mean progression-free survival duration of 28.7 weeks was significantly longer than that of historic controls.20 o Floxuridine (5-fluoro 2'-deoxyuridine [FUDR]), 5-fluorouracil (5-FU), and vinblastine, paclitaxel (Taxol), carboplatin, ifosfamide, gemcitabine, and anthracycline (doxorubicin) all have been used. Floxuridine infusion has a mean response rate of 12%, while vinblastine infusion yielded an overall response rate of 7%. 5-FU alone has a response rate of 10%, but when used in combination with interferon, it had a 19% response rate in some studies. o Renal cell carcinoma is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p -glycoprotein. Normal renal proximal tubules and renal cell carcinoma both express high levels of p -glycoprotein. Calcium channel blockers or other drugs that interfere with the function of p -glycoprotein can diminish resistance to vinblastine and anthracycline in human renal cell carcinoma cell lines. * Biologic therapies o The interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. The interferons have a direct antiproliferative effect on renal tumor cells in vitro, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. Interferon-alpha, which is derived from leukocytes, has an objective response rate of approximately 15% (range 0-29%). o Preclinical studies have shown synergy between interferons and cytotoxic drugs. In several prospective randomized trials, combinations do not appear to provide major advantages over single-agent therapy. Many different types and preparations of interferons have been used without any difference in efficacy. o IL-2 is a T-cell growth factor and activator of T cells and natural killer cells. IL-2 affects tumor growth by activating lymphoid cells in vivo without affecting tumor proliferation directly. + In the initial study by the National Cancer Institute, bolus intravenous infusions of high-dose IL-2 combined with lymphokine-activated killer (LAK) cells produced objective response rates of 33%. In subsequent multicenter trials, the response rate was 16%. Subsequent studies also showed that LAK cells add no definite therapeutic benefit and can be eliminated from the treatment.21 A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) resulted in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months. Eighty percent of patients who responded completely to therapy with IL-2 were alive at 10 years. + Most patients responded after the first cycle, and those who did not respond after the second cycle did not respond to any further treatment. Therefore, the current recommendation is to continue treatment with high-dose IL-2 to best response (up to 6 cycles) or until toxic effects become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-FU have not been shown to be more effective than high-dose IL-2 alone. + Toxic effects associated with high-dose IL-2 are related to increased vascular permeability and secondary cytokine secretion (eg, IL-1, interferon gamma, tumor necrosis factor, nitric oxide). The management of high-dose IL-2 toxicities requires inpatient monitoring, often in an intensive care unit. # The major toxic effect of high-dose IL-2 is a sepsislike syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak. # Other toxic effects are fever, chills, fatigue, infection, and hypotension. # High-dose IL-2 has been associated with a 1-4% incidence of treatment-related death and should be offered only to patients with no cardiac ischemia or significant impairment of renal or pulmonary functions. Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from the capillary leak. This syndrome is normally reversible. * Treatment strategies o For early stage renal cell carcinoma, an emerging treatment strategy is to utilize these molecular approaches earlier in the adjuvant setting in order to improve overall survival rates. Indeed, a randomized phase 3 trial of sunitinib versus sorafenib versus placebo as adjuvant therapy in patients with resected renal cell carcinoma is currently ongoing and open for patient enrollment.22 o The optimal sequence or combination of active agents in advanced renal cell carcinoma is not yet defined. Based on decisions derived from level 1 evidence, the following may be considered as reasonable targeted therapy choices in patients with metastatic renal cell carcinoma who are not eligible for high-dose IL-2 therapy. + For previously untreated patients with clear cell renal cell cancer of low or intermediate risk, sunitinib or the combination of bevacizumab and interferon alpha + For patients with previously untreated clear cell renal cell cancer with poor prognostic (high-risk) characteristics, temsirolimus + For patients with previously treated clear cell renal cell cancer, sorafenib; if standard doses fail, an increase in dose may produce responses; patients in whom sorafenib is failing may be treated with sunitinib if that drug had not been previously used. + The treatment of metastatic renal cell carcinoma is problematic, and, wherever possible, patients should be directed to approved and controlled clinical trials. This applies as well in the adjuvant treatment of surgically resected renal cell carcinoma, for which no therapy has yet been found to offer survival benefit. o High-dose interleukin-2 must be considered for robust patients with excellent cardiopulmonary reserve, as it remains the only treatment known to induce complete and durable remissions, albeit in a minority of patients. Prospective studies are underway to identify patients more likely to respond to interleukin-2 immunotherapy based on carbonic anhydrase IX expression in the primary tumor and other assessments of immune function and regulation. This study may help to resolve the sequence and selection of available agents for individual patients with metastatic disease. o Future treatment strategies for advanced renal cell carcinoma will likely incorporate a combination of molecular approaches, using multidrug regimens consisting of small-molecule kinase inhibitors with biologic therapies, immunomodulatory therapies, or both. * Other experimental approaches for treatment include immunomodulatory drugs, vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation. o The immunomodulator lenalidomide (Revlimid), a derivative of thalidomide, inhibits VEGF, stimulates T and NK cells, and inhibits inflammatory cytokines. It has been evaluated extensively in hematologic malignancies. In phase 2 studies of metastatic renal cell carcinoma, it demonstrated an antitumor effect in some cases, with disease stabilization or durable partial response.23,24 o Vaccine trials are in early stages of development. Few antigens have been identified that induce T-cell responses from renal cell carcinoma. One example of vaccine strategy is to induce the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) into autologous cultured renal cell cancer lines by retroviral transduction. Patients then are immunized with irradiated tumor cells secreting large amounts of GM-CSF and are evaluated for immune responses and clinical tumor regression. Other approaches to vaccination include tumor lysates and dendritic cells. Autologous vaccine therapy is now being tried in combination with cytokine therapy. A pilot study of vaccinating with the corresponding mutant von Hippel-Lindau peptides demonstrated safety and proved efficacy in generating a specific immune response in patients with advanced renal cell carcinoma.25 o Nonmyeloablative allogeneic stem cell transplantation is another research approach. This can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen (HLA)-identical sibling or a sibling with a mismatch of a single HLA antigen. Patients with no response received as many as 3 infusions of donor lymphocytes. Two patients died of transplantation-related causes, and 8 died from progressive disease. In 10 patients (53%), metastatic disease regressed; 3 patients had a complete response, and 7 had a partial response. The durations of these responses continue to be assessed. Further trials are needed to confirm these findings and to evaluate long-term benefits. * Multiple studies have been conducted using megestrol (Megace) in the treatment of renal cell carcinoma. No benefit has been shown except for appetite stimulation, so megestrol is currently not recommended. Antiestrogens such as tamoxifen (100 mg/m2/d or more) and toremifene (300 mg/d) also have been tried, with a response rate as low as that of most chemotherapeutic agents. Surgical Care Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease. * Radical nephrectomy, which remains the most commonly performed standard surgical procedure today for treatment of localized renal carcinoma, involves complete removal of the Gerota fascia and its contents, including a resection of kidney, perirenal fat, and ipsilateral adrenal gland, with or without ipsilateral lymph node dissection. Radical nephrectomy provides a better surgical margin than simple removal of the kidney, since perinephric fat may be involved in some patients. Twenty to thirty percent of patients with clinically localized disease develop metastatic disease after nephrectomy. Some surgeons believe that the adrenal gland should not be removed because of the low probability of ipsilateral adrenal metastasis and the morbidity associated with adrenalectomy. In the absence of distant metastatic disease with locally extensive and invasive tumors, adjacent structures such as bowel, spleen, or psoas muscle may be excised en bloc during radical nephrectomy. o Lymph nodes may be involved in 10-25% of patients. The 5-year survival rate in patients with regional node involvement is substantially lower than in patients with stage I or II disease. Regional lymphadenectomy adds little in terms of operative time or risk and should be included in conjunction with radical nephrectomy. o Approximately 5% of patients with renal cell carcinoma have inferior vena caval involvement. Tumor invasion of the renal vein and inferior vena cava usually occurs as a well-vascularized thrombus covered with its own intimal surface. In patients with renal vein involvement without metastases, radical nephrectomy is performed with early ligation of the renal artery but no manipulation of the renal vein. If the inferior vena cava is involved, then vascular control of the inferior vena cava is obtained both above and below the tumor thrombus, and the thrombus is resected intact, with subsequent closure of the vena cava. Patients with actual invasion of the inferior vena caval wall have poor prognoses, despite aggressive surgical approaches. o At least 3 common approaches exist for removal of kidney cancer, as follows: (1) the transperitoneal approach, (2) the flank approach, and (3) the thoracoabdominal approach. Approach depends on tumor location and size and the body habitus of the patient. The thoracoabdominal approach offers the advantage of palpation of the ipsilateral lung cavity and mediastinum, as well as the ability to resect solitary pulmonary metastases. * Laparoscopic nephrectomy is a less invasive procedure, incurs less morbidity, and is associated with shorter recovery time and less blood loss. The need for pain medications is reduced, but operating room time and costs are higher. Disadvantages include concerns about spillage and technical difficulties in defining surgical margins. Laparoscopic partial nephrectomy can be considered at centers with experience in this procedure for early stage renal cell cancer. * Palliative nephrectomy should be considered in patients with metastatic disease for alleviation of symptoms such as pain, hemorrhage, malaise, hypercalcemia, erythrocytosis, or hypertension. Several randomized studies are now showing improved overall survival in patients presenting with metastatic kidney cancer who have nephrectomy followed by either interferon or IL-2. If the patient has good physiological status, then nephrectomy should be performed prior to immunotherapy. Reports have documented regression of metastatic renal cell carcinoma after removal of the primary tumor. Adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments. * Renal artery embolization with ethanol and gelatin sponge pledgets has been found effective for palliative treatment in patients who are not candidates for surgery, or who refuse surgery. A retrospective study in 8 patients with stage IV disease found that ethanol ablation controlled hematuria and flank pain.26 * About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis. Surgical resection is recommended in selected patients with metastatic renal carcinoma. This procedure may not be curative in all patients but may produce some long-term survivors. The possibility of disease-free survival increases after resection of primary tumor and isolated metastasis excision. * Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery, either because of extensive disease or poor overall condition. o A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy. o Preoperative radiation therapy yields no survival advantage. o Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with perinephric fat extension, adrenal invasion, or involved margins. A dose of 4500 cGy is delivered, with consideration of a boost. o Palliative radiation therapy is often used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurological progression. Surgery also should be considered for solitary brain or spine lesions, followed by postoperative radiotherapy. * About 11% of patients develop brain metastasis during the course of illness. Renal cell carcinoma is a radioresistant tumor, but radiation treatment of brain metastasis improves quality of life, local control, and overall survival duration. Patients with untreated brain metastasis have a median survival time of 1 month, which can be improved with glucocorticoid therapy and brain irradiation. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions. Consultations * Urology * Oncology * Radiation oncology Medication The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications. Antineoplastic agents Few options are available for the systemic therapy of renal cell carcinoma, and no hormonal or chemotherapeutic regimen is accepted as a standard of care to treat renal cell carcinoma. Objective response rates, either for single or combination chemotherapy, usually are lower than 15%. Multikinase inhibitors induce objective responses in up to 40% of patients, but they are not known to cure patients with metastatic disease. Aldesleukin (Proleukin) IL-2; T-cell growth factor and activator of T cells and natural killer cells. Affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly. * Dosing * Interactions * Contraindications * Precautions Adult 600,000-720,000 IU/kg q8h for as many as 5 d or per protocol Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Corticosteroids may decrease antitumor effect; NSAIDs increase capillary leak syndrome; potentiates effects of antihypertensive medications * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment May cause sepsislike syndrome due to "capillary leak"; other toxic effects are flulike syndrome, fever, chills, fatigue, infection, myelosuppression, hepatic toxicity, neurological and neuropsychiatric findings, hypotension, erythema, rash, urticaria, and alteration in thyroid function (including hyperthyroidism and hypothyroidism); high-dose IL-2 has been associated with treatment-related deaths Vinblastine (Velban, Alkaban-AQ) Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation. * Dosing * Interactions * Contraindications * Precautions Adult Per protocol Pediatric Not established * Dosing * Interactions * Contraindications * Precautions May reduce phenytoin plasma levels; mitomycin-C may increase toxicity significantly * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; IT use may result in death; severe bone marrow suppression; uncontrolled bacterial infection * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions IT use may result in death Dose-limiting toxicity is myelosuppression; other toxic effects include nausea, vomiting, alopecia, neurologic effects, local skin damage (if extravasated) Gemcitabine (Gemzar) Cytidine analog. After intracellular metabolism to active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. * Dosing * Interactions * Contraindications * Precautions Adult Per protocol Pediatric Not established * Dosing * Interactions * Contraindications * Precautions None reported * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions May cause myelosuppression (particularly thrombocytopenia); toxic effects include flulike syndrome, LFT abnormalities, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic-uremic syndrome 5-fluorouracil (Adrucil) Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. Has cell-cycle specificity with activity in S phase. Inhibits thymidylate synthase by 5-FU metabolite F-dUMP. Metabolite FUTMP incorporates into RNA and F-dUTP incorporates into DNA, resulting in alteration of RNA processing and inhibition of DNA synthesis. * Dosing * Interactions * Contraindications * Precautions Adult Per protocol Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; other immunosuppressants exacerbate bone marrow toxicity; leucovorin enhances toxicity and antitumor activity when given before 5-FU; antifolate analogs (methotrexate and trimetrexate) increase formation of 5-FU metabolite; thymidine and uridine rescue host toxic effect * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; poor nutritional status; myelosuppression * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (eg, bone marrow suppression) may occur; main toxic effects include myelosuppression, mucositis, diarrhea, metallic taste in mouth, hand-foot syndrome, alopecia, dermatitis, increased pigmentation, cerebellar ataxia, somnolence, confusion, seizure, rarely acute encephalopathy, chest pain syndrome, ECG changes, cardiac enzyme elevation, blepharitis, tear duct stenosis, and cholestatic jaundice with biliary stenosis Sorafenib (Nexavar) First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for advanced renal cell carcinoma. * Dosing * Interactions * Contraindications * Precautions Adult 400 mg PO bid 1 h ac or 2 h pc Pediatric Not established * Dosing * Interactions * Contraindications * Precautions CYP450 2B6 and 2C8 inhibitor; predominantly eliminated by UGT1A1 pathway (caution when coadministered with other drugs eliminated by UGT1A1 [eg, irinotecan]); coadministration with warfarin may increase INR or bleeding * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Common adverse reactions include hand or foot skin reaction and rash (modify dose); may increase risk of hemorrhage, cardiac ischemia and/or infarction, alopecia, pruritus, or diarrhea; caution with severe hepatic impairment (ie, Child-Pugh C) Sunitinib (Sutent) Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET). Indicated for advanced renal cell carcinoma. * Dosing * Interactions * Contraindications * Precautions Adult Standard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Potent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently) * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; concurrent administration with St John's wort * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Common adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may prolong QT interval, which may lead to Torsade de Pointes; may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding Temsirolimus (Torisel) Water soluble ester of sirolimus. Binds with high affinity to immunophilin FKBP (FK506 binding protein). This complex inhibits mammalian target of rapamycin (mTOR) kinase, a key protein in cells that regulates gene translation responsible for cell cycle regulation. mTOR also reduces cell growth factors (eg, vascular endothelial growth factor) involved in new blood vessel development. Indicated for advanced renal cell carcinoma. * Dosing * Interactions * Contraindications * Precautions Adult 25 mg IV qwk infused over 30-60 min Pediatric Not established * Dosing * Interactions * Contraindications * Precautions CYP3A4/5 inducers (eg, rifampin) may decrease serum levels and thereby decrease efficacy; CYP3A4 inhibitors (eg, ketoconazole) may increase serum levels and thereby increase toxicity * Dosing * Interactions * Contraindications * Precautions None known * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Pretreat with antihistamine; common adverse effects include rash, fatigue, mucositis, nausea, edema, and anorexia; common laboratory abnormalities include hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase and serum creatinine values, hypophosphatemia, anemia, leukopenia, and thrombocytopenia; hypersensitivity reactions (eg, anaphylaxis, dyspnea, flushing, chest pain) have been reported (discontinue infusion and treat with antihistamine; at physician discretion, may restart at slower infusion rate); also reported are rare occurrences of bowel perforation, interstitial lung disease (discontinue and consider treating with corticosteroids and/or antibiotics), and renal failure (monitor renal function at baseline and during therapy); infection may result from immunosuppression Everolimus (Afinitor) Rapamycin-derivative kinase inhibitor. Indicated for advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Reduces cell proliferation and angiogenesis by inhibition of mTOR pathway. * Dosing * Interactions * Contraindications * Precautions Adult 10 mg PO qd Hepatic impairment (ie, Child-Pugh class B): 5 mg PO qd Coadministration with strong CYP3A4 inducers: Increase dose by 5-mg increments, not to exceed 20 mg/d Treatment interruption and/or dose reduction to 5 mg/d may be required to manage adverse drug effects Pediatric Not established * Dosing * Interactions * Contraindications * Precautions CYP3A4 substrate; PgP substrate and moderate inhibitor; competitive inhibitor of CYP3A4 and mixed inhibitor of CYP2D6 Moderate-to-strong CYP3A4 inhibitors or PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem) may increase blood concentrations and should be avoided if possible CYP3A4 and PgP inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease blood concentrations and require an increase in dose * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity to everolimus or other rapamycin derivatives; avoid coadministration with moderate-to-strong CYP3A4 or PgP inhibitors; Child-Pugh class C hepatic impairment * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions May cause infections, oral mucositis, and noninfectious pneumonitis; common adverse effects (>30%) include stomatitis, infections, asthenia, fatigue, cough, and diarrhea; common laboratory abnormalities (>50%) include anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased serum creatinine levels

Interferon alfa 2a (Roferon A) and 2b (Intron A)

Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties.
They have direct antiproliferative effect on renal tumor cells, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

6 million IU/m2 SC in combination with low-dose IL-2 or per protocol
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Inhibits antitumor effects of cyclophosphamide; increases effects of phenytoin and phenobarbital; theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; vaccination with live vaccine during and for 3 mo after completion of therapy

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in brain metastases, severe hepatic or renal insufficiency, seizure disorders, multiple sclerosis, or compromised CNS; main toxic effects include flulike syndrome, fatigue, anorexia, somnolence, confusion, depression, myelosuppression, mild and transient elevation in serum transaminases, mild proteinuria, hypocalcemia, acute renal failure, nephrotic syndrome, alopecia rashes, pruritus, irritation at injection site, chest pain, arrhythmias, congestive heart failure, impotence, decreased libido, menstrual irregularities, and increased incidence of spontaneous abortion

Pazopanib (Votrient)

Multityrosine kinase inhibitor. Indicated for advanced renal cell carcinoma.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

800 mg PO qd on empty stomach (at least 1 h ac or 2 h pc)
Baseline moderate hepatic impairment: 200 mg PO qd
Do not crush or chew (increases bioavailability and absorption rate, with possible increased toxicity)
Food also increases bioavailability, possibly resulting in increased toxicity
Pediatric

Not establishedFollow-up
Further Outpatient Care

* For stage I and II disease, complete history, physical examination, chest radiographs, liver function tests, BUN and creatinine, and calcium are recommended every 6 months for 2 years, then annually for 5 years. Abdominal CT scan is recommended once at 4-6 months and then as indicated.
* For stage III renal cell carcinoma, physical examination, chest radiographs, liver function tests, BUN and creatinine, and calcium are recommended every 4 months for 2 years, every 6 months for 3 years, and then annually for 5 years. Abdominal CT scan should be performed at 4-6 months, then annually or as indicated.
* Spontaneous regression has been reported anecdotally in renal cell carcinoma. As many as 10% of patients with metastatic disease show no progression for more than 12 months. All systemic therapies are associated with treatment-related toxicity and low response, so close observation is an option for asymptomatic metastatic disease. Once evidence of progression or symptoms appears, appropriate therapy should be initiated.
* Careful surveillance of patients with end-stage renal disease by ultrasonography and CT scan is recommended.

Deterrence/Prevention

* Avoidance of causative factors such as smoking, obesity, and other factors as described in Causes is recommended.
* Careful surveillance of patients with end-stage renal disease or VHL disease, those who have undergone renal transplantation, and other high-risk groups by ultrasonography and CT scan is recommended.

Complications

Excruciating, sharp, bandlike back pain may be an early warning for spinal cord compression due to metastatic renal cell carcinoma and should not be ignored. Urgent MRI should be performed to rule out cord compression, and high-dose dexamethasone therapy should be started.

Prognosis

* Five-year survival rates are as follows:
o After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%. Patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis.
o The 5-year disease-specific survival rate in patients with T1 renal carcinoma is 95% and in those with stage T2 disease, 88%. Patients with T3 renal carcinoma have a 5-year survival rate of 59%, and those with T4 disease had a 5-year disease-specific survival rate of 20%.
o Patients with regional lymph node involvement or extracapsular extension have a survival rate of 12-25%. Although renal vein involvement does not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB renal cell carcinoma is 18%. In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate is 25-50%.
o Five-year survival rates for patients with stage IV disease are low (0-20%).
* Motzer et al identified 5 prognostic factors for predicting survival in patients with metastatic renal-cell carcinoma.27 These factors were used to categorize patients with metastatic renal cell carcinoma into 3 risk groups. Patients in the favorable-risk group (zero risk factors) had a median survival of 20 months. Patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, while patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. The prognostic factors were as follows:
o Low Karnofsky performance status (<80%) o High serum lactate dehydrogenase level (>1.5 times upper limit of normal)
o Low hemoglobin (below lower limit of normal)
o High "corrected" serum calcium (>10 mg/dL)
o No prior nephrectomy
* Factors associated with increased survival in patients with metastatic disease are as follows: (1) a long disease-free interval between initial nephrectomy and the appearance of metastases, (2) the presence of only pulmonary metastases, (3) good performance status, and (4) removal of the primary tumor.

Patient Education

* Patients in the high-risk group should be made aware of the early signs and symptoms and the need for early intervention for possible cure should be stressed.
* Patients in early stages who have undergone treatment should be educated about possible relapse.
* For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Blood in the Urine and Renal Cell Cancer.

Miscellaneous
Medicolegal Pitfalls

* In 25-30% of patients, renal cell carcinoma is asymptomatic and found incidentally on a radiologic study.
* A renal mass of indeterminate etiology should be monitored periodically by imaging study; intravenous pyelography (IVP), ultrasound, or CT scan. A cystic mass can be simply observed. Patients with a solid mass should have a complete workup, including evaluation for metastatic disease and vascular extension of the primary tumor.
* As many as one third of patients with clinically localized disease may develop metastatic disease after nephrectomy, so they should be monitored carefully.
* The major medical pitfall is ignoring a solid renal mass and failing to provide appropriate follow-up care.

Special Concerns

Renal cell carcinoma develops in nearly 40% of patients with VHL disease and is a major cause of death in patients with VHL disease. VHL disease and other hereditary forms are transmitted in an autosomal dominant manner. Family members of patients with these syndromes should be educated about familial multiple-cancer syndrome, and genetic counseling should be offered to the patients and family members.